The present invention provides a process for the preparation of N-{(1S)-1-[2-(1-{[(3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidin-3-yl]carbonyl}piperidin-4-yl)-5-chlorophenyl]ethyl}acetamide (Compound I)
and crystalline salts, hydrates and polymorphs thereof.
Compound I is a selective melanocortin 4 receptor agonist useful for the treatment, control, or prevention of disorders responsive to the activation of MC-4R, such as obesity, obesity-related disorders, diabetes, metabolic syndrome, male sexual dysfunction, including erectile dysfunction, and female sexual dysfunction.
International Patent Application No. WO 02/068388 and US Patent Publication No. 2003/0225060 disclose Compound I and a process for its preparation. While the crystal forms produced in WO 02/068388 and US Patent Publication No. 2003/0225060 are not specifically addressed, the disclosed processes for the preparation of Compound I in these applications yield Compound I as an amorphous free base and as an amorphous mono hydrochloride salt. Neither the free base nor the amorphous salt is ideal for pharmaceutical formulation. The free base is unstable, photosensitive and thermally sensitive, and subject to oxidation if stored at a temperature greater than −40° C. The amorphous mono hydrochloride salt, formed by lyophilization or spray drying, is difficult to purify and has poor flow properties. It is therefore desirable to obtain crystalline forms of Compound I with improved physical and chemical stability, and fewer impurities for the preparation of a solid pharmaceutical dosage forms containing Compound I as the active pharmaceutical ingredient.